The 20% rarest cancers account for approximately 35% of the deaths from cancer in the United States. As a result, a better understanding of the nature of these rare tumors is in the public health's best interest. We study sarcomas, rare cancers of connective tissue: bone, muscle, fat, cartilage, and the other tissues that hold us together. These are cancers that occur disproportionately in children, teens, and young adults, although different forms affect different age groups. In all, sarcomas account for less than 1% of all cancer in the United States. However, since they can arise from so many different tissues, there are 70 or more sarcoma subtypes. We are interested in finding new treatments for the people with these rare cancers, who do not benefit from research on more common cancers. We have identified two new combinations of drugs that may be useful for people with sarcoma. The first of these is A12, an "insulin-like growth factor 1 receptor" inhibitor, and temsirolimus, an mTOR inhibitor. The second is a blocker of Hh (hedgehog) signaling, GDC-0449, which we are combining with a blocker of gamma secretase (RO4929097) [Notch pathway] in a novel study for people with recurrent sarcomas. We are seeking funding to perform this multi-center study, focusing on biopsies from patients on these two studies for biological correlates of blockade of these various pathways. These biopsies will help us determine would or would not benefit from such therapy. We will also use a software tool we have recently developed, called StudyTracker, to collect the data from the multiple participating centers on the GDC-0449/RO4929097 phase I-II study. With this information, we will be able to use tests of tumors to insure that the right person is receiving the right medication, with the best chance of getting a good result from that treatment. Without such testing, clinical trials are reduced to "throwing darts"-some people could benefit, but we will not understand why. This approach should lead to new and efficient means to treat patients with sarcomas and may also impact patients with more common cancers. PUBLIC HEALTH RELEVANCE: This is a project to support correlative studies for two multicenter clinical trials of new drugs for patients with sarcomas. These novel approaches will improve the treatment options for this underserved group of patients with this rare family of cancers